“( June 21, 1996- . #

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___
“uEcEIvEcI BY rHC
OFFICE (IF sp~f~L
wR/TK)HA~&-n~..,:$-~.so
~ETAPHARW
Natural PreventiveHcahhcare
xAmlPluqkc
WJCXSCY
Ayi)uc,
B..Sui@l”.
~u~~i~
New Bnmsvick. Nl W901.3279:..
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June 21, 1996-
Dr. Ekabeth;
Yetky, Director
0i3ice of Special Nutritional HFS450
Center for Food Safety and Applied Nutrition
Food and Drug Administration
200 C StrX N.W.
Washington D.C. 20204
.
#
●
:.
Dear Dr. Yetley
Notkeis hereby given purmant to the requirements ofSection403(r)(6) (21 U.S.C. 343 (r)(6))
oftheFedeml F@ Drug and Cosmetic Act of Statements of nutritional support which have
been made on the label and in the labeling in connection with the marketing of the dietary
supplement Melatonin1mgwithViB-61
mg @let Mektonin 1 mg with Vitamin B-6
1 mgtabl~ packagedin blister ptlOkwill be first marketed with these statement of nutritional
support on July 1, W96. The statements of nutritional support areas follow
.
Bliiter Pack ~bel:
For restoring normal sleep in individuals whose natural melatonin has been
take 1 tablet at bedtimq or as directed by your health care profmsional.
DIRECTION&
alt-
WARNINGS: TAKE ONLY ONE TABLET PER DAY. NOT FOR CHILDREN UNDER
18. DO NOT USE IF PREGNANT OR NURSING, OR IF TRYING TO CONCEIVE (BOTH
MEN AND WOMEN). FOR RELIEF OF OCCASIONAL SLEEPLESSNESS.
IF
SLEEPLESSNESS PERSISTS CONTINUOUSLY FOR MORE THAN 2 WEEKS,
CONSULT YOUR DOCTOR DO NOT TAKE THIS PRODUCT IF YOU ARE TAKING
SEDATIVES OR TRANQUILIZERS OR UNDER MEDICATION WITHOUT
CONSULTING YOUR DOCTOR (SEE ENCLOSED INSERT).*
97s”o/4-
.’
-
/--=-
Dr. Ebabeth
Director
Oflice of Special Nutritional
Page 2
June 21, 1996
& Yetky,
.
-.
.
Melatonin helps regulate your sleep cycle resultingin quality sleep. This is espeokdly useiid for
travel- and shift workers. This product is also an excellent. source of vii
B-6 yhich is needed
for your body’s natural abiity to produce mehitonin.*
x-~
sTA~
S HAVE NOT BEEN EVALUATED BY THE FOOD AND
DRUG ADMLNISTIUTION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE,
TREAT, CURE, OR PREVENT ANY DISEASE.
A Label copy is attached.
Labelings:
Number 1:
Introducing Melatonin with Wamin B-6 Nutritional Supplement*
We are pleased to offkr Melatonin - Low Do= containing lmg of Melatonin and lmg of Vkunin
B-6.
●
●
●
●
Melatouin: Helps to regulate the onset and quality of sleep, especially in those individuals
whose natural abiity to produce melatonin has been altered.”
I%w-Dosage Because consumer safety is our primary conce~
lmg effective
,. dose.
our Melatonin comes in a
Vitamin B-6: Maintainsthe body’s mtural abiity to produce Melatonin.
For Shift Workers and Travelem: Mdatonin is particularly usefid for those who have their
light patterns disrupted-such as shiil workers, travelers across time zon~ and individuals
with dficulty ad~sting to seasonal changes in dayh.ight length.
.“,
-
Dr. Ekabeth A Yetky, Mreotor
OfEce of Special Nutritional
Page 3 ~
June 21, 1996
-.
.
●
Lower-Dose Option: Tablets are scored for the option of 0.5mg.
em
s’rA~
.
HAVE NOT BEEN EVALUATED BY THE FOOD ANDDRUG
ADMINISTRATION. THIS PRODUCT IS NOT INTENDEDTO DIAGNOSQ TREAT,
CURIjOR PREVENTANY DISEASE.
●
A Labeling copy is attached.
1.
Dollins et al. Effkct of inducing nooturmd serum melatonin concentration in daytime sleep,
rno@ bodytemperaturej and pdormance. ProcNatl Acad Sci USA 1*,91:1824-1828.
2.
Zhdanova et al. Slgep-induc%g eflbots of low doses of melatonin ingested in the evening.
ClinPharmacol Ther. 1995;57:5512-S58.
Number2and3:
-
There’s melaton@ and now there’s MeIatonin from XetaPharmTM,IK
Melatonin helps regulate your sleep oyclq resulting in quality sleep. This is especially uselid for
traveks and shiil workers. Also, as you age your body’s production of melatonin slowly decrm
ofbm leadingto sleep dkurbanoes. Soientitic data indioates that supplementing witli melatonin may
help prevent th-esesleep disturbances.*
This product is also a source of Vi
produce melatonin.*
B-6, which is needed for your body’s natural ability to
Our Melatonin
Low Dosage*
●
●
Because consumer tiety is our primary condose112.
Tablets are scored for the lower-dosage
our Melatonin mmes in an effective lmg
option of 0.5mg.
r
.
Dr. Ekabeth A Yetley, Director
Office of Special Nutritional
Page 4
June 21, 1996
..
.
Purest Grade*
.
●
●
●
Pr6duct is prepared with the purest grade of Melatonin and Vi
.
B-6 av@able.
.
Fiied
products are tested for potency, puxity, weight variatio% disintegration%and
dissolution as per Nutritional Supplemen@ Uni&dSt@s Pharmacopoeia(USP).
fl
Products are manufktured with the same care and quality control necessary for a
pharmaceutical product.
~
STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG
ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE TREAT,
CURE OR PREVENT ANY DISEASE.
Labeling copies are attached.’
1. Dollins et al. E&xx of inducing nocturnal serum melatonin concentration in daytime sleep,
mod body temperature and pefiormance. Proc Natl Aoad Sci USA 1994;91: 1824-1828.
2. ZManova et al. Sleep-inducing effkzts of low doses of melatonin ingested in the evening. Clin
Pharmacol Ther. 1995;57:5512-558.
Very truly yours,
Xet.aP~
Inc.
A subsidiary of
Xeche~ International Inc.
~“
Ramesh ChandraPandey, Ph.D.
President and CEO
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There%mel.atoniq
and now therek Melatonin
fkomXetaPharnf’,Inc
Melatonin helps regulate your sleep cycle, resulting b. quality sleep. This
is especidy useful for tmvelem and shift workers. AISO,as you ag%your
body%production of mclatonin slowly decmascs, often leading to sleep
disturbances. scientific data indicates that supplementing with mclatonin
my help p~ellt these Skp disturbances.*
.
.
This product is also a source of Vhnin B-6, which is needed f;r”your body%
natural ability to produce melatonin~
#
Our MeIatonin
●
Low-Dosage*
Becauseconsumer safety is our primary concern, our Melatonin comes
●
in an effective lmg dosel~.
. Tablets are scored for the lowerdosage option of 0.5mg.
Grade*
Product is prepared with the purest grade of Melatoqin and ~lm
B-6 avdable.
Purest
●
●
Finished products am tested for poten~, pmity, weight variatio~
disintcgratio~ and dissolution as per Nutritional Supplements,
United States Phamtacopeia (USP).
●
Products am mamdhctured with the same cam and QualitYcontrol
..-
necessay for a pharmaceutical product.
Gold Leaf
EmIldchallenge
-~l=w
-afthisb&nd LsVawabti
These statements have not been evaluated by the Food and Dmg Mmidstmdon.
- This productis not inte+d @-&gnosqQeaL~
or pmv~t my disease
●
-
“-~~
outsidetcsttng
kbomtoryintkworId.
“Mektonin is available itz.bdes of 90 tublets,
and ako in Travder Packs of 10 tubkts. To place your oni.ercdl
Customer savice at 1-800-858-58S4
XETAPCIARM
NaturalPreventiveHedthcare
kc
xdaPharm’1
A subsidiary ofxcchun. Intcrnatiod k.
100Jmcy Avenue
Buildiig B. Suite 310
NCW Bmnswids NJ 08901-3279
TEL (908) 249-0133 FAX (90S) 2474090
OmmudOn
10dba4EUrxt0(indudng nmumd-aclltOda
~w=+.ti~y—w—m
andpdemw% R’OcNdAad Sdum. 19M$M824-1628.
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We are pleased to offer Melatonin-Low
D= containing lmg of Melatonin and lmg
of vitamin B-d.
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Melatonim Helps to regulatethe onset
and quality of sleep, especidy h those
indivihls whose naturalability to produce
pnelatonin
hasbeen ahimd.1~
o
●
.
..
●
●
LOvv-Dosagc2Becauseconsumer safety is
our Mekttonin
&mprimary conq
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and manufkcturhtg nutritional supplements
as go into our phmmaceutial product%
We measure quality w$h only one yardstick
.
.“
.
...””
Maintainsthe bodyk
natural ability to produce Melatonin.
)
We folIowastrictcode ofethicstnmgards
to label Ch’CCtiOIIS, declarations of identity
strength and purity, daily intake valu~
conditions of usq and warnings
●
Purest Grade productis prepared
with
thepuxestgrade of Mekmoninand Vitamin
B-6 avaitabk
●
Potency, Puriw Pinished products are
tested for potelq Pm’@ weight Vatiatioq
disintegration and dissolution as per
Nutritional Supplements, UMtedStates
Phmmuc@a (usP).
.
For Shift Workersand Tkavelers
●
hb T~e& Mommy control and test
proeedurea are designed to assure that
the componexmqin-process matetials,
label% and finished products conform
to appypiate Standatdaof identiq, stren~
quality, and purity
.
Fnmtx&Phann”, hlc
&
. .
XetaPharnrdemands that the same rigid
quality standards must go into developing
Vitankt
B-&
Mehorh is particularly useful for those
who have thetr light patterns dismptedsuch as shift workem, travelersacross
time zones, and indMdds with diflkmlty
adjusting to seasonal changes in
Ck#nig,htlength.
,.,.,.
.;.:.
● Low&Dose
optioru
.,,K,
I,
J!!?
.*=fl
oTablti are scored for the
option of 0.5mg.
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NutritionalSu pkments,
Hlarnlaceuticl standards.
comes in a lmg effectivedose.
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IntroducingMelatoni.n
with ~ltiilllh
B-6
NutritionalSupplement*
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.
.
#
●
1.
Dolhs et al.
Effit of inducing nocturnal serum melatonin
concentrations in daytime sleep, mood body temperature and
performance. Proc. Natl. Acad. Sci. 91,1824-1828,1994.
.
pmt.
Nad. Acad. Set USA
Vd. 91, PP. 1824-1828.March 1994
physiology
3
Effect of inducing nocturnal serum melatonin concentrations in
daytime on sIeep, mood, body temperature, and performance
(ddi-df8@4vwW*dti)
ANDREW B. DOLLINS*, IRINA V. ZHDANOVA,RtCHARDJ. WURTMANt, HARRY-J.LYNCH, AND M= H. DENG
tkpmsn@ai
Camnsu
Bdsand
Gxmisiw SdCGUS. MBSsdsussm tssstituteof Tedmotow. Cambsi@. MA tlZ139
tsicatedby Walk J. H. Nauta, November 23,1993 {received for review July 20, lk3)
#
We’examined effects of very kJW doses of
ABsrRAcr
mdatonin (0.1-10 mg,.oraiiy)or placebo, admiaktcrcd at1145
h, on sleep latency and duration, mood, performance, oral
temperatuset and changes IISserum mcktonin kveis in 20
doubie-btiad
healthy mate ~oluntecrs. A repeated—measure
a bate of
Latin square design was used. SubjectsCQmPiCtCKi
tests designedWasstss moodand pClfO~CC between 0930
and 1730 h. The sedative-likeeffectsofmeiatonin wereascssed
by a $impIedeep test at 1330 h subjectswere asked to bold a
positive pressure switch ineachhand andtoreiaxwitbeyes
dosed while recliningin ● qukt darkeaedroan Latencyand
dumtion of switch release+indicatorsofskep, were measured.
Areas under the timenwlatonin concentrationcurve varied in
proportion to the different meiatoniadosrs ingested, and the
0.1- and 0.3-mg doses generatedpeak serum meiatonk kveis
kveis
that werewkhin the normalrangeofnocturd mdsstoaill
b untreatedpcopk.M mektoaia doses tested s@iik@ly
kcmascdskp duratioq as Wdiassdf-repod akepincasaad
fdigq diltk to @ilCdIO.Moswwx, d of the doses s@ifand
kallt!y &crcasd Skepousct latenq, oral tenlpcmm
wiikboo ●dkory
thcmsmbcrofco
mcctrcsponsesoothe
TigiMce task. Tbescdata ildicsStcthat
oratiydmIukmd
mclatoain an bcabighly pokothypaotic agcnqthcyako
auggcstthatthepbsidogkdbcreas
eimserum
mdatodn
kve&whkho ccumaround2100h daily,mayamstitutc
Signal initiating normal Skcp ollseL
●
serum mdat(min levels in normal humans ale Vuy low
during most ofthc day but incmaacSignitlcantlyto a mean of
80 pg/ml (range,*MO) between0200and 0400h (1 pg/ml =
4.31
pmol/liter) and remaincl-~cd duringthe normaIhours
Skal@y to daytime dues
around ()$@ h (l).
l%e physiologicalsi@kancc of the nocwmal incmasc in
Of SkCf.), fai@
serum mdatonin could derive tim acute effects of the
hormone [e.g., its ability to reduce core body temperature
Q). ~ter tie~o~htion
(3), modiiy brain kveis of m-
1
amine neurotmnsmittcrs (4), stimulate prolactin accretion
(S), or induce skcpincss (6, 7)].
.
Altcmativcly, the nocturnal increase-in serum mdatonin
could constitute a time sig@, affecting the temporal characteristics of other circadian rhythms. Oscillations in the
concentmtion of circulating mdatonin could directly affect
ckadian rhythms (8, 9) or could provide humorai coinmunication of information about environmental lighting (and
thus about time of day), which entrains endogenous physiological and behavioral rhythms (e.g., those associated with
photopcriodism or scasonaiity; ref. 10). some studies also
suggest a role for mciatonin in human development. The
decrease in amplitude of the melatonin rhythm, which occurs
late in the 1st decade of life, has been proposed as a factor
contributing to pubescence (11), while further decrease,
of this suticlc
The poblicdon COSIS
payment. This tick
;- .-,-,.4 .--* w:,h
were dcfsaycd in pas-sby page charge
must tlwcfore bc hcsrby marked.“udvcrrismwsf*’
Ifl ! T < P
$1774 .oTe Iv ,n ;mA;ea, C ,h;< far,
which occurs after the 6th decade, &y contributeto dq
tions in circadian rhythmkity reportedby the ddcrly (12).
The acute cffbctsof exogenousmektonin on human k
havior have &en studied onlYsporadiiy and have used
mciatonin doses that rake scmm mdatonin levels well be-
yond their normal nocturnalrange.IIXIS,LAu7nanetd
“
(13) found that a dose (240 mg over a 2-h period) that raised
serum meiatonin kvds several thousandfoldimpairedmood
and pCIfOMWCC. More r’eccdy, wCfOUtId
SiMiiWbdtatiorai
changes after a cmnsidcrablylower dose of the hormone (10
mg),whii still raisedserumkveisto4050timcs thenormai
noctumai kvci (i.e., 4072 pg/mi; ref. 14).
The present study was designed to dctcrminc whether
much lower daythne doses, which elevate serum mdatonin
but keep these kvcla within the normal
kvds Si@fkdy
nocturnal range, arc @so Suflkient to produce abort-term
bchavioraici%cts.Ifso,thiswouIdsuggcstaaitnikrrokfm
thcnormalnoctumd iWrCaWinsctltmlWIxOOhkv&
gave the mektodn atmidday (9amoreb
noctumd=mcrcasc)andmcasmcdmpccf~
incss, and (indirectly) skcp onset.
before the
skcp
M33THODS
m MA’mRxUs
TWcnty hcaithy male volunteers [mean age, 23.05 = 4.22
(SEM) .y~,
range, 18-24 yCIU%]
participate k)cfote admission to the study, each subjcctgavc his htformcdco~
hadaphyskai examination tocnsurc that bcwasitt~
to become
health, and contpktui tWO M-b _acsskns
fawithtcst.ing
procedtues andtheperfortnaw
testbattery. subjects Wre also screened f- depressive sytnptoms by using the -ton
p@lktdC rat@ acak fm
depression (M) with a special addendumfor seasonal affGctive disorder;
any with a histo~ orfe
of dcpmsskn
were excluded. Ail subjects were paid for thdr participation
in the experiment.
The study was double blind and pIaccbo controU&. A
rcpcatcd-mcasttrcs,within-subjects, 5 x 5 Latin square design w& used. TiIc subjects paticipatcd in five 8-h (093&
1730 h) testing sessions. At least 5 days elapsed between
successive test sessions. Capsules containing 0.1,0.3,1.0, or
10mgof mciatonin orpiacebo wcm adtniniitcrcd odiy (p.o.)
at 1145 h each test &y. Treatmentorder m determinedby
the balanced Ixitin square design.
Orai temperatures were measured hourly and biood was
sampIed at rcgukr intervals via an indwdiii”venous catheter
for subsequent serum melatonin measurement. Serum sampies were separated by centrifugation and stored at -WC
Abbreviations: P.O., Odfi
RT, SCSW+OO time; POMS, proiik of
mocd sfaks; SSS. Stanford slccpincssscale.
%-cscnt address: DoD Polygraph Institute, Bufi@ 3~5. FLMc~Cbn. AL 36205.
-f’To whom rcpsint requests should bc ackksscd ac Massachusct~“lnstit,!te of Technolow. E2S-604. Cambridte. MA 02139.
Physiology Dollins et af.
)
Ptvc. NatL Acad. Sci. USA 91 (199$)
undi thCYCOUMbc SSSSyCCt
by radioinununoasaayfor melatanln (In.
‘fltroughout~est SCssions,aubjccts were requ”d to sit at
wOfk*tiOtl with CYCSOpCSt.~C task
_*
qtm
ordcrand time oftcsting WCrCheldconstant across test days.
N instru@ons, performance tasks, and mood questionnaires were automated to rcducc the possttity of expcrilIWItCdtldUCCd
bk.
lk
@WttWtCC
tasks
used WCf’C
in-house and included rncasyrcs of (i) auditory vigilsncc(18), (ii) four-choi~ SCSC~On
time (RT)(~)t (fi9 simPk
RT. and(iv) symbol digit(modalities)substitution(20). Mood
questknnaircs included the profde of mood states (POMS;
rd. 21) am! the Stanford slqincss scale (SSS; ref. 22).
&tails of the tasks and th+r administrationarc published
clscwhcrc (24). The mood questionnaireswere compkted at
1030hand at hourlyintervalsbeginningat 1200h. The simple
andfdur-choiceRTs andsymbol digitsubstitution tasks were
compktcd at 1030,2300 MOO,1600,and 1700h. Theauditoty
vigbcc task was adAtcrcd
at 1200and 1400 h. Subjects
were allowed to kave their workstations during lunch (a
standardlunch was scnfcd bctwccn 1100 and 1130 h), toilet
breaks (- rein), and duringthe half-hour skcp tcsc
subjects participatedin a sleep test bctwccn 2330and 1400
h ‘Ilwy were asked to recline(oneither a bed or a nxlining
coded
.
chair)and relax with their eyes closed in a quiet, darkened
mom In each handthey held a l-in (254 cm) plastic tube that
hose apositiveprcssurc switch. ‘fltcy were asked to test their
hands, palm up, aIongside their body and to depress the
awkchcs with the last segmentof their index f~ers. Rekasc
oftiac swkch on cithcrtubc was nxordcd as a pca dcfkction
oaan event rccdcr. An investigatorremainedin attendance
that they followedinstructions.
with the subjects to Cnsurc
~
Aa CVatt-tintersoknoid wss randomlyactivated to dUCC
wotddbc
thepossiiility
thatthc
aoftdkkof thesw itch
mkonstmcd by the subjectsas a s“@dfkantevcnL After 30
m& the subjects were asked to stop relaxing and/or were
awakened. They were then asked (i) if they f~ askep. (iin if
m,ti@htakti
Md=p,
md(m@~W@wti
SSS. Latency to switch rckasc was measured from the
~-of
i~ction~cn~tionto
the firatfidl minute of
switch rclcasc. Total switchrckasc time was measuredas the
total kngth of time a recording pcn was dcfkctcd (the
atnallcat intctval of pcn deflection measured was 1 ttdn;
WXWWY.OX rein). Onc subject med to rckasc a switch
dudaga sleep test session butwas identified as asleep by his
-d
snofins. skp onset for WE subjcctwas rccotxkd
as occwring afkcr 2 min of continuous snoring. When questioned later, the sub~ repotted that he had indeed fden
*.
The after-trcatmentdepcndcnt measures were each assessed by using a repeated-tncasurcs, Witiln-subjects. 5 x 5
Latinsquareanalysis. Orthogonalplannedcomparisons (23)
west! used to evaluate dticrenccs among the melatonin/
treatment conditions when a significant (P c 0.0S)
pbbo
tmattnent effkct was found. The comparisons chosen were(i)
placebo vs. all mclatonin treatments,(ii) 0.1 vs. 0.3.1.0, and
10 tngof mclatonin. (iii) 0.3 vs. 1.0 and 10 mg of melatonin,
and (iv) 1.0 vs. 10 mg of melatonin. Pairwisc comparisons
WCresubsequently calculated for these measures (rcpcatedmcasures t tests for the sleep test and melatonin data and
ANOVAS for the other measures) because inspection of the
daa suggested tha( the planned comparisons provided an
insufiicien[ basis for interpreting results. Only main effects
I
that resulted in significant contrasts and interaction effects
zuc reported. TI-JCm
were some missing data due (o dficuhies
with equipmen(. croup means were therefore subs(inned for
the 1700-h (0.1 mg). 1300-h (1.0 mg), 1700-h (1.0 mg). and
l~h
(10 mg) Measures for subjects 15.03.16.
~d 15.
ttspcctivc[y, on most pcrforrnancc measures. Blood samples
WcrC not drown durina nlaccbo [cstin~ of subicct 01 due to
-1825
difficulties with cathctcrization, and groupmeans were sub-
stituted for the data. Group means of serummclatoninlevels
were also substituted for six other mussingdata points. The
Gteek syt@ol A ~ used to indicate “an avemge change of.,”
.
REsuLm-”
,
Suum Mctatosdn Levels. Mean serum melatonin levels arc
ihstratcd in Fii. 1. The man (SEM) areas under the
tirnmlatonitt conccntmtion curve (AUC) bctwccn 1000
and 1730 h for the placebo and 0.1-, 0.3-, 1.0-, and ltl-mg
treatment conditions wcm 87.7 (5.11), 213.2 (2S.02), 4S99
(62.7), 2S99.0 (141.7), and 21,000.4 (37523), I’CSpCCtiV~y.
Serum melatcminAUC differed significandyamong the five
=
34.34;
P C 0.001) and all
treatment conditions (J74*
planned contrasts were signKcant (P < 0.001). All painvisc
comparisonswere also significant(P c 0.001).The order and
treatment-by-ordercfkcts were not signikant.
Mctatonin TYcatmcnt EffcctQ Sign&ant mclatonin treatment cffccta were found for otzdtcmpcratqm(Fw40 = 7.S0;
P< O.UU);skcp test skcp-onset Iatency (F’(im = 6.6S; P <
0.001);skcp duration(F(fm = 7.80;P < 0.001);self-icportcd
skc~nsct latency (F(f~ = 10.52;P C 0.(01): postskcp test
SSS responses (Fwm = 3.11; P < 0.05) @ii. 2k ~MS
vigor-activity (Fwa = 4.16; P < 0.01) and fatigue+crtia
U?(4XOI
= 3.M J’ < 0.0S) (F%. 3) rcspon-, SSS responses
(Fa~ = 2.7%P< 0.0S); numberofcorrcct rcapottscson the
WMnson auditoty vigilance task (F(f@j = 3.4Z P <0.0$,
and four-choke RT response latency (F(fm) = 3.84; P <
0.01). Table 1 summarizes the planned compsrkoa results
and Table 2 contains the mean (SEM) Iev+ measured. TIM
treatment-by-order interaction effects were nonsignificant
for alI mcasums”except the Sss (F(4#3 “ 4.68; P < 0.001).
‘nHc were no significant diffksencca among the baseline
(1000h)otaltcmpcrature, SSSOorFOMs mcasm AttOtdCr
cffcctwaa found among the four-choi~ RTrcsponac latency
baadinc mcasuma (FH~ = 2S.23; P < 0.001), but the
treatment and tmatmcnt-by+xdcr intctaclion effects were
nons”-L
As Table 2 indicates, response kvcls for some measures
did not consktcmly incteasc or dcaease dative to serum
mclatoninkvets. For cxampk, self-rcportqdSSS responses
weregreatestandPOMSvigor-activityscaletesponscawere
stnakst tics ingesting0.3 mg, rather than higherdosca, of
mclatonin. Pahisc comparisonswere caktdatcd to aid in
intcrp~tion ofthesedata. Meanoral tcmpcmtturcmcasurca
werestgnifkantlykss, relativeto placebo,afteringesting1.0
and 10 mg of mc[atonin[A -0.24°F and -0.37F, rcspcc10000
E
H
=
E
>
a.
A
0.0 mg
0.1 mg
p
A
o.s
:
mg
1.0 mg
+ 10.0 mg
I
I
1000
1
1200
...“.* . . ...*
..”””+.
-+
;
0
1000
----
;
I
1
1400
1600
Clock +iOUf
FIG. 1. Mcari (SEM) serum mclatonin profiles of 20 subjects
sampled at in(emtals after ingesting 0.1. 0.3, 1.0, and 10 mg of
mclatonin or placctm at 1145 h.
.
●
.-.
Physiology
1826
n
Dollins et uJ.
Pr~
A
m
4.5
25
[A
15
t
.
A
.B
:’20
10
Nut!. Acad. SCL USA 91 (1994)
f
4.0
15
r/\\\,
ts
l.klh
3.5
10
o
LELb
.0 0.1 0.s 1.0 10.0
0.0 0.1
S.o
2.5
.010.0
B
14
Molatodnc
w
FIG. 2. Mcaw(SEM)sleep-on=t ~tcti$ (A). $Ieepd~tin$
(B). adf-rqxtcd sleep-onsetMc*
(C). and posttcst SSS responses(D) aftcria.gcsdonof melatoidnorplaccbo at 1145 h (n - 20).
12
tivelfi 1°F = CC x 9/5) + 321.H temwmmms m~
after ingesting LO (A -0.16Y7 and 10 (A -0.2Y~ mg of
mclatonin wcte also less thanthose measuredafter ingestion
of O.1mg of tnelatortin.Ingestionof 10mgof melatottinaIso
10
dccmascd oral temperaturerelative to the 03- and l.o-mg
doses (A -0.21T and -0.13”F, rCS~tiV~y).
SSS responses
)
.
indicated greater feelings of slccpincss, relative to placebo,
after ingesting 0.3, 1.0, and 10 mg of meIatonin (A +0.S1,
+0.47, and +0.46, respectively). POMS responses showed a
decrease insclf-reported fedngs of vigor+wtivity, rclativeto
pbCCbO,after Ittgcst@ 0.3, LO, and 10 mg ofutclatonitt (A
-N7. -190. and -1.95, t’CSpd@y). Fcclinga of @oractivi&ywcrcalso dccmascdaftcriagcsting03 mgtdativeto
1.0 tng ofmclatottin (A -1.33). POMS.ms_.indi!i~e~
&crcasc ittscff%cportcdfeuttgs of~
-,
a
ht8c$tig 0.3,1.0, and 10 mg of melatonist (A
+214, +1.S6, and +2.28, -Vdy).
Skcp test dq
onset latenck-s were Shottcr, relative to placebo, *
itt-7.4S, -9.03,
g@@ O.LO.3, 1.0, ~d 10m80f mhti(A
-11.02, and -10.32 tnin, respectively). The duration ofslccp
(i.e., switch rclcasc) cxpcdcnccd dusing the sleep test was
greater, relative to placebo, forthc 0.1-,03-,1.0-, and lo-mg
mclatotdtt doses (A +8.20, +10.04, +22.09, and +10.47 ndn,
respectively). Sleep test sclf%cportcddeep latencics were
smaller, relative to phwcbo, forthe 0.1-,0.3-, LO-,and lo-mg
mclatonittdoses (A -7.60,-10.60,-23.27,
and -10.65 mist).
Subjects also indicated that they slept more quickly after
ingesting 1.0 trig,relative to 0.1 mg, ofmdatonitt (A -5.67).
Responses to thepostsleep test SSS indbte that subjects felt
sleepier after ingesting 1.0 and 10 tngof mclatonin than after
ingesting pklCCbO
(A +0.70 and +0.95, respectively). Wstslecp test SSS responses also inditite that LO mg of mclatonin caused greater feelings of sleepiness than 0.1 mg (A
+0.70). Fewer Wdkinson auditow vigilance task correct
responses were recorded, relative to placebo, after subjects
ingested 1.0 and 10 mg of tnelatonin (A -4.75 and -S.67,
respectively). Correct four-choice RT response latencica
were greater (i.e., longer) after ingesting 10 mg, relative to
placebo, and 0.1 mg of melatonin (A +17.21 and +14.46 ma,
respectively).
All of the painvkc comparison. results reported
above were signifxant at the P <0.05 level.
Order and Tic Effects. Sign&ant order effects wem
found on the Wilkinson auditory vigilance, simple RT, fourchoice RT, and symbol digit substitution tasks. Thcsc rcstdts
indicate that subjects tended to respond mot-c accumtely
(symbol digit substitution responses and RT response latcncics) with practice and ICSSfrequently (WiWinson auditory
B
.
.
8
1
c
..●.
$-u.
,~
1000
1200
Clock
1400
1600
~OUC
3. Mean response scores on-the .Sss (A), ~~
V&OCl%.
activity scale (B), and POMS tkti@Hnma Scslcs(c) throughout
testing.Mctatordnor @XCbO was in&stcd
at 1145h (n = 20).
breascd feelingsof stccpincss,vigor,and fatiguearc indicatedby
higher scores.
Wanc@on subsequent test days. ‘Ike changes arc oflittlc
interest because (i) significant treatment-by-order intcfactions were not fwnd on these tncas~
(h? the Latin square
is balanced to compensate for order effcds, and (iii) similar
rc$wh.shave been observed previously (14).
There WC= consistent patterns of VariiinCCover time
among the mood scale measures. Subjects’ SSS (Fo.m =
17.50; p < 0.001) ~d ~MS fatigue-inc& (F(s.73 = 8.04; P
< O.(Ktl)NSpOnSCSindi~te hat they felt sleepiest d most
fatigued and that they felt the least vigorous mMS vigoractivity scale (5379 = 12.79; P < 0.001)] at 1400 h. 2.25 h
after mekitonin hgcstion @ii. 3). Oral temperatures WCrC
consistently ]OW at H(l(j md 1400 h (mCans, %.8YF and
PhydoIow Dolhs et UL
ProG NatL Acad
Tabk L McstI diffuenccs ofptanncdcompakM f-s-t
M vs. 0.1,03,
1.0,and10
-Q~**
Orat tcmpcratum,●F
0.42””
s!xPrOfiks)fmood states
.=..
vii-activity scale
1.75””
Fat@c-kstss“ scste
stsxp test
Steqwwt latency,miss
SCL VSA 91 (1994)
ovaan F-ts
0.1 vs. 0.3:1.0.
o.3v&l.oandlo
and10
-0.14””
-0.28””
“
0.25’”
-0.0s””
-.
-0.77’”
0.97””
0.84””
-o.22””-
1827
.
14 vs. 10
-0.33
-0.01
-0.0s
0.72
-9,4**
1020””
-10.s3””
0.61””
-2.67”” ‘
-1.64””
0.70
2.67””
~ 1.24””
,
-1.62
tip dmin
-1.36””
-3.91””
2.62
sctf~stccp
tatcncy,min
0.0s””
,-0.40”
0.48”” .
=~.
WikmsOn●ditOry Vi@ncc.
-3.33*
-3.03
-219”
-0.92”
Corrcu Iespomics
Four-choiceRT
10.06””
U.25
7.s7”
2.62*
cOITcctresponselatcsscy,MS
vd~btimaav
mdtiwbmtm~t
ib(dtiub--=bti-a
comnadsonawwe Ftcstscalculatd wW5and15dc8secsofkd XSGn
=20(scc kxtfordctailaofsnksin8 value
●
subskutiona). ●. P < O.@,●c, P <0.001.
97.@T, rcspdvcly). Meanfour+At&c RTresponselatcncics were the greatest at 2300h (i.e., 377.77MS)and dccrcascdto 360.2SMSat 1700h. Significanttreatment-by-time
hlteradons Werefoundin Od tunpclaturc (F(’S4.%S) = 1.60;
P< O.OS)and numbcrofcorrcctsespo~ onthefw-choice
RT task (Z@soj = 1.92; P < 0.0S).
DISCUSSION
-n
?f snclatottin(0.1-10 mg) at 1145 h dtd
in
cmqmnd@y
kreascd circulating tnclatonin kvcls. scSum melatottin Concctttnltions Obaclwd after the 0.1- and
O.%ngdoscs wcrcwithin thettormaldyttdc
rangcfm
nodurnd snclatonin concentrations (1). Sleep test results
hdicatc that acute adminktratiostof mclatdn (0.1-10 mg,
pa) at midday krcascd objective and Sclfwcpmtcdsleep
ostsct latcnoks by an averageof 9.46 and 10.S3mist,rcspccti@y, relative to P&do. SIccpduration was krcascd by
an average of 10.2 mistduringthe 30-tninsleep test, teladve
toplaccbo,byingcstionof mclatottin.Paitwkccotnparisonof
SSS scores, stftcrthe skcp tcs~ indicates that the 0.3- and
LO-mgdosca oftnclatonin incnmcd self-reportedfcdings of
akcplncsa, rclrstivcto placebo, and that feelingsof slccphtcss
afterthc l.(kssgdoscwcrc gmatcrthan those aftertheO.l+ng
“Tksc results indicatethatingestion of anacutedose of
mclatonitt, sufficient to imxcasc circulating mciatonin to
within the normal nocturnal physiologic range, has
lCVCIS
hypnotic effects. The acute nature of the hypnotic cfkt of
mclatoninsuggests that it may constitute a directphysiologic
cfikct of the honnonc independent of its actionas a circadm
by
zcit@scrtime Si#lid (2426). ‘ThiS hypothesis is SUpWItCd
the rcccnt independent observation that rnclatonin(S trig,
p.o.) administeredat 1200,1700, or 1900 h cxatcd a direct
hypnotic effccG isicmdng sleep propensity withii 90-220
min of ingestion (27). The phase shifts in ckadian rhythms
its sleep (27) or cndogcnous mclatottin sccmtion (28, 29)
-Y
scco after a single acute dose ofthc hormone, as
used ~
w~ of iasttfficieat magnitude to support the
hypothds thattbc hypnotic cfkctsfd
inthccttrrcnt
study cotUdbcatttscdby mclatonittactingas aze@cbcrtimc
signaI.Suchahypothcsia would suggcstthata9-h phascahift
in slccponsctcanoccuraftcra sis@eacutcdoscofmclatonht
at m“ddafi this scents MgMyitnptvbable
The obsctvcd signiit
dccmasca iaotaltcmpcratum
ttftcringestion of 1.0 and 10 tng of mclatonin arc cott!dstcnt
with previous reports (’2, 14). Alterations in ntood and pcrrntancc mcasurca after mclatottin ingestion, relative to
kbo
(C.g., incmasc in fdngs of slwpincas and fatigue;
dcacasc in fangs of
incrcaw in four-tltoid RT latc~
vigor, dccrcasc in number of correct responses on the Wilkistson auditoty vi@ancc task), arc also consistent with
previous reports in both dwction and magnitudeofsncasurc
(13, 14).The direction and magnitude of response change,
relative to p[accbo, among the melatonin doses administered
Table 2. hkan (SEM)measuredresponses
Mctatoniningested,mg
W
tcsnpcrwm, “F
0.0
97*5 (0.06)
3.IS (0.10)
0.1
97.47(0.06)
3.38 (0.10)
0.3
97.39(0.0s)
3.66(0.10)
1.0
97.31(0.05)
3.62 (0.12)
10.0
97.18(0.0S)
3.61(0.13)
12.73(0.S9)
11.29 (0.64)
9.% (0.57)
10.83(0.65)
10.78(0.63)
3.83 (0.40)
4.85 (0.42)
5.97 (0.44)
5.39(0.49)
6.11 (0.53)
R&k. of moodstates
Vlgor+ctivity scale
Fatigue-inertia scale
sleep test
Sleep-onset Is4ency. min
Sleep duration. min
Scif-reported sleep lalcncy,
min
SSS rcspomes
Wilkinson auditory vigilance,
comcct responses
Four-choice RT
corrcc[ rcspmssc Iatcncy. ms
17.06(2.43)
9.61 (1.84)
8.03 (1.60)
6.04 (1-65)
6.74 (1.24)
11.36 (2.34)
19.56 (1.79)
21.40 (1.63)
23.45 (1.67)
21.83 (1.41)
20.55 (2.23)
3.80 (0.22)
12.95 (2.07)
4.05 (0.26)
9.95 (1.69)
4.s0 (0.22)
7.28 (1.33)
4.75 (0.25)
9.90 (2.07)
4.35 (0.26)
27.30 (1.48)
25.85 (1.32)
24.28(1.53)
22.55(1.66)
21.63 (1.56)
359.41
(8.2S)
359S4(7.36)
367.74(7.65)
374.03(9.08)
376.62
(9.86)
.=-
1828
were consistent on both the mood and pcrformattcc tncasurcs. [t thus seems likely that failure to fti si.gnifiit
differences in mood or pcrfbsmanccbetween placebo andthe
lower mctatonin doses (0.1 and 0.3 mg) is due to the limited
sensitivity of the measures used rather than an abscncc of
Ctrect.
The results of thk study arc consistent with the observations of Vollrath et aL (6). who rcpon a decrease in daytime.
latency of sleep onset in subjects given 1.7 w of melatonin
nasally and with those of Lavie and COkgWX WI dcscrii
above.
Nickelscn etd. (30)rcpomd W m m Ofmelatonin,
administered p.o. at 0900 or 1900 h, caused nonsignifkant
decreases in sleep latency but increased feelings ofslccpincss
only after the administration at 0900 h. Others (31, 32)
reported that evening ingestionof mchtonh(1 and S W) did
not influence sleep onset or duration but did csusc an
incmasc in rapideye movement (REM) sleep-onset latency.
These studies suggest that the magnkude of mclatonin’s
sedative-like effects may be significantly influenced by the
time of its administration. Alternatively, the cxpctimental
designs used itf the negative studies might have precluded
observing the hypnotic effect seen here (e.g., by not allowing
subjects to modify thcii sleep times or by forbiddingafternoon napping; rcfs. 28 and 29). It should bc noted that the
pattern of physiologic and performance responses observed
here resembles that obsemd fordrugsin the bcnzodiazcpine
family (33-3s).
In summary, administration of a small mclatonin dose
(0.1-0.3 mg, p.o.) during the daytime, which raises serum
tttclatonin concentrations to within the normal nocturnal
range, or of sliitly highcrdoscs (LO-1OW, p.o.) was shown
to cause hypnotic effects KhltivC tO pkCbO. _
effects
include adccrcasc in objective andself-cstimt cd slq-onset
latency. an incmasc in sleep duration, and skcpincss upon
waking. Sclfwcportcd feelings of sleepiness and fatigue were
increased and fcdings of vigor diminished.Od tcmpcratum
and the number of correct responses on the W-n
ttuditoty vigilancetask wcm found to decrease signifiidy
after ingestionof 1.0 and 10tng of melatonin.These results
arc similar to those repotted after ingestion of bcnzodiazcpittcs and suggestthat tttclatonintnayfindusc as a hypnotic
dtug. TINYalsosuggestthat the normalphysiologicsecretion
of melatoninmaybean importantand direct-actingfactorin
bringingabout skcp onset.
Thcauthors wish toexprcss special thsnksto thesubjects who
participated in the study, ths Massachusetts InstituteofTdmalogy
Clinical Rcscamh center nursing staff, and Ms. Yilun I% for
assistsmxthroughoutthedatacoktion. This study was suppastcd
in part by grants from the U.S. Air Force (AFOSR90-012Sand
AFOSR 90-0326), the Nahnai Aeronauticsand Space AdtnWtration (NAG 9-14). the Center for Brain Scicrsccs and Mctabolisrn
ChasitabteTrust,the Nationalhssthte of MentalHoakh(MHS114$
01), and the National Institutesof Hcatth to the Clinical Research
center at Massachusetts Instituteof Tcchnotogy (MO1-RROO088).
Lynch, H. J., Brzczkiski. A.. Dcng, M. H.& Licbcrmaa, H.
(1987) in Advances in Pineal Research. ed$. Frsschini, F. &
Reitcr. R J. (Liibcy, London). Vet. 2, pp. 181-189.
2. Cagnacci, A.. Eltiott, J. A. & Yen, S. S. C. (1992) J. Clin.
L
Endocrinol. Metab. 75,447-452.
3.
vkvanathsn,
M.. Laitinen, J. T. & Saavcdm, J. M. (1990)
Proc. lVatl. Acad. Sci. USA 87, 62CQ-6203.
4.
5.
.
Physiology Dollirtset U;
Anton-Tay. F.. Chou. C.. Anton. S. & Wurunan.R. J. (1968)
Science 162,277-278.
WaJdhauscr, F., Lick-man, H. R., Lynch, H. J., Watdhauscr,
PrO-A>atL Acad. Sci. USA 91 (1994]
M.. Hcskna. K.. FsischiH...vii.
R. J. &-s
Schctnpcr.M.. Wum.
6.
7.
8.
9.
10.
11.
H.. Wddhaust, W.,
W. F. (19S7)Nae
rocn&rinology 46.125-130.
vothth. L., Scmm.P. & Gamsnct.G. (1981)Adv. Biosri. ~,
.
327-329.
wtwman. R. L & LicbcrsnsmH. (1987)hucgr. Psychiix~ q
13-14.
J. M.(1991)Adv.pineal
LewY. A. J.. sack. R. L. A ~~.
Res. S, 285-293.
‘J. M. L. & sSCtG R. L
LCWY.A. J., Ahtncd.S.. J*-.
(1992) Chronobw. InI. 9,380-392.
Rcitcr. R. J. (1988) ia Melistonin:CCnlcalPerspectives. eds.
Mica. A., Phiibti% D. R S. &Thompson,C. (Oxfbrdhif.
New York). pp. 1-42.
bss,
Watdhauscr, F.. Wciszcnhscha. G., Frisch, H., tith~,
U.. Watdhbcr. M. & W&tman. R. J. (1984) Lancer L 362-
J. W..
12. ?%islcr. C. A., Durnont. M.. Dfsffy, J. F., Stein~
Richardson;G. S., Brown, E. N.. Sanchez R. Rios, C. D. &
Rod& J. M. (1992) ti~ct 340.933-936.
13. Licbaman, H. R.. Watdtsauscr.F., GarfickI,G..LynckH.J.
&Wurtman,R. J. (1984)Erath Rcs. 323,201-207.
14. Doltins, A. B., Lynch, H. J., Wumnam R. J.. Dcng. M. H.,
Kjschk K. U.. Gleason, R. E. & Licbamart, H. R (1993)
Psychophysiology 11% 490-4%.
2s. Hamilton, M. (1%7) Br. J. Sot. Clin. PsychoL ~ 278-296.
16. Roscnthat, N. E., Gcnhsrt, M.. Sack, D. A., skewer,R G.&
Wehr, T. A. (1987) in 271ePsychobiology ~ Bulimia, ok
Hudson, J. L& POPC,H. G., Jr. (Am. Psychiatr.Press, Wdsington, DC), pp. 265-228.
17. Brzezinski, A.. sciil, M. M.. Lync& H. J., Dcng,M.H.&
Wurtrnan.R J. f2987)J. Cfin.Endachol. Merab. 64,865-867.
18. Wilkinson, R T. (l%!l) Psycho/. Bull. 72s 260-272.
19. wilkinsom R. T. & Houghton, D. 097S) Behav. Res. Me&a%
Instrum. 7,441-446.
20. Smith,A. (2967)E&c. Psywhol. Mess. 27,1077-1083.
L F. (1~) J%@
21. McNair,P. M., Lorr,M. & DroPPkmsII,
of MoodStates Manual(Educationsad IndssstWTcstiog
22.
sciviCc.San Diego).
Haddcs,E., DemcnGW. & ~
Ob?gy10,431-436.
V. (2973)Psyc@hysi-
23.
W=, B. J. (2971) Staddical Ptiacipks in Espdnetud
sign (McGraw-HilL New York), 2std Ed. pp. 384-388.
24.
2s.
Asendt,
L & Broadway. J. (2987)ChIVnobiaf.ht. 4, 2734D.
De
Pcuic, K., Conagl&I,J. VqlWnpsom L&*_K
(2989)Br. Med. J. 29& W-707.
26. Ctaustrat, B.. Brun, J., David, M., Sassotas,G. & Chat. G.
(1992)Biol. Psychiaoy 3% 70S-711.
27. Tzischinski. Q.. bvle. P. & Pal. I. (2992) J. Sleep Ra. 1,
Suppl. 1, m..
28. Lcwy. A. J. & sack R L (2993)in Me&toninapdthe@netd
Gkand. ji-om Bask S&tce 10 Clinical Appkariam cds..
Tiitou. Y.. Arm&. J.& Pcvct. Y. fElscvi~Scicncc. Amsta-). PP. =210. 29. Zaidart,R.. GeofMau, M.. ClaustsaLB., BruinJ.. Taillar&J..
Bureau, C. & ChaZ@ G. (2993) in Mdatonits and the ~al
Gland, jktn
Basic Science
to Clinical Applicatk
eds.
Tiiitou, Y., Amndt. J. & PCVCLY. (EIscvicr Scicncc Pub
fishers B.V.. Amsterdam), pp. 23%339.
30. Nickctscn, T.. Dcmisch, L., Dcmisch, K.. Radermacha. B. &
Schoffting,K. (1989) J. PineaJ Res. 6, 32S-334.
31. James, S. P.. Mcndelson. W. B., Sack. D. A., Rosenthal,
1,
N. E. & Wehr, T. A. (2987) NeUrop$ychoPti~off
41-44.
32. kUllCS, S. P., Sack. D. A.. Rosenthal, N. E. & Mcssdctsao.
W. B. (1990) Neuropsychaphamtocology 3, 19-23.
33. Koelcga, H. S. (1989) Psychopharmacology 98, 145-2%.
34. Grecnblau, D. J.. Harmatz. J. S., Engelhardt, N. & Sbada.
R. L (1989) Arch. Gen. J%ycitiufry 46, 32&332.
35. Watsh.J. K.. Schweitzer. P. K. & Parwstikcr. S. (1983)Ciin.
Pharmacol. Ther. 34,496-500.
‘
n
---
.
-.
.
.
# .
●
2.
.)
Zhdanova et al. Sleep-inducing effixts of low doses of melatonin
ingested in the evening. Clin. Pharmacol. ‘l%erap.57,552-558,
1995.
.
?
PHARMA CODYNAMICS
DRUG ACTION
AND .
.
Sleep-inducing effects of low-dosti of
melatonin ingested in the evening ‘ W4previouslyobsenwd that low oral doses of rnelatonin given at noon in~
b[ood melatonin connoeturdyand
fkilitateslcep o~a$assessdtd.ng
aninvolcentrations to dmsc normdy _
sethe induction of po~pthisstudyweaamined
unczymuscle relaxation -In
corded sleep bysimilar ”dosesgiven later inthccvcrdng, dosetothe
times ofdogenma
mdatoado
release and habitual sleep onset Vohmtcas received the hormooe (oral doses of 0.3 or 1.0 mg) or
bat~8,0r9r~
~tiAmsIqo~
~~2d~4timpid
~mo~t~d~
were measured polyxmnogm pMy.B&*~atayof&c&tiph@~*
2 $kq. Melatonin did not SUPPreSS~
S!eCp or tiy
its OnSeC
OllSCtkncy and iatcncy to ~
Most volunteers could clearly dkingukh betwan the effkaa of mch.onin and those of
pla-
placebo
when
tictim-
tiat60r8~~&tia
m&*~~~~~q=~
tests ahinistdon
Withmoodandpafknallce
thceafkrtreamwn&l
hcSedat2pvkktlew
scauionmay beinvolvcd inphysiologic slecponslx 2ndthstcx0ge.
nousmelatonin may beasefid intrcatiaghsomms. “-(G.Q4 PaUwUxm k
199$57:552-8.)
evidence that nocturnal
melatoti.
Irina V. ~&llO~
I?hl), Richard
J; W~
MD, Harry J. Lyn4 PhD,
J&n IL Iv-B% Andrew B. Doll& PhD, Claudia Morabitq BS, .
ad-Mm.
Jean K Matheso& MD, and Donald L Schema, MD -c
In the initial description of mdatocin (S-mcthoxyMcetyltxyptatnine) as the mclanophore lightening
agent present in bovine pineaI glands, the hormone’s
Fmmthc Clii
Rcscard Gntrrand2kparmuof
Braioaod
Mxs@mem Ins&weof Tcchnotogy,CamW*
-.
bridge,and he Dcpamnm[of Neumtogy.Beth fsrad Hospkd,
HamsrdMcdicd Sehoot,h“
Suppmtcdbymscuchgnntsfmmthe Nstioaaltnsti~of&aftb,
Becbcs4 Md. (MH-5114S) aod.* Centerfor Bnio seimces
Cambridge, kss. Stud”ks
sod Maabotiim Charitabk T-
waecoo&ckd a(ttKGmenf
~useasImtimtcofT~M
Clinii
RcseamhCeatcrat&c
by agrant
(RRO008S)hO(bCNXiOOd thUXfWRti
RcsouKe.
Nationallnsriwcsof HcatIIL
Raxivcd fw pubticatiooAug. 29, l% xcepted Nov. 15.1994.
ReprintGXJUCS& RiCfWId J. Wurunan, MD, Cd H- GmcnDistin~
of Braind CO@tivc scknccs,
g@hcd Pmfti.
Masxbuwu fnstiNtcof Tcchno!ogy.E&604, 45 (3rtemn St..
CUnhidgc. MA 02142.
Copy@N Q 1995by Mosby-Year Boo&. tnc.
M39-92349SfS3.CO+ O 13/(/620s3
552
-
1
sedative effect on humans ti
noted.’ Although melatoain was subsequently shown to k seeRtcd primaruy
at night, when people sleep,2 its mle in physiologic
sleep remained uncertain.3PbrmaeOlogic doses of the
hormone, Which inemase serum melatonin levels far
beyond theii normal noeturmdrange, eotdd be shown
to produce hypnti”c cffeets in humans*: however,
Sllli3kf doses WXii@’ tcSed and yielded inconsistent results when examined.’~ We started by testing
the midday administration of a phmnaeologic dose
(240 mg, administered orally) of mclatonin and, on
the basii of perfomlanee tests and SeIf-rcpom, obsenfed hypnotic-like cffeets. ‘0 We next tested four
much lower (but still pharmacologic) doses of the hormone (10, 20, 40, or 80 mg) or placebo, given at
noon. Although the resulting mean serum melatonin
mncentrations were ~ugtiy proportionalto the do=
administered, all doses wem equally effective,
Axive
to placebo, in induckg
subjdvc
sleepiness. ‘1’hcsc
in decreasing
oral
doses wem aISO equd]y cffw(ive
“
“
.
)
~,
~
the number of correct responses in audi-
Self.rcporud Vigor.11Because the
cffbcts were not dated to dose, we concluded that the
.
.
btockmd
moehaniims that mediate the behavioral
(and temperature)effects of melatoninhad been saturated by tdl of the doses tested. In further pursuit of
this line of investigation, we examined the effects of
much lower oml doses (i.e., 1.0, 0.3, and 0.1 mg of
me!atonin or p[acdxx compafcd with a 10.0 mg refercncc dose) administereda} noqn. Sleep onw and duration wetc studied beginning 1V4hours after the addnistration of melatonin ok placebo by means of a
~gflancc,and
positive pressure switch technique.iz serum melatonin
concentrations wete,~again, ioughly proportional to
dose, but the peak amplitudes Obsetwd after the 0.1
0.3 mg doses (mean a SEM, 48.4 * 37.1 and
121.45 “a 24.21, respectively)wem withh the nomud
(noetud) range for human serum melatonin levels.
Sleep onset Iatencics *; ingestion of any of the
doses tested were significantlyshorter than those after
ingestionof pladw peak effects were observed with
the 0.3 mg and 1.0 mg doses. Thii study was designed to determinewhethersuch doses also facilitate
skcp onset when given in the evening, close to the
hour that most people elect to skcp, and whether the
hypnoticeffect of the hormonecao be detected @yand
)
somnogmphkauy.
METHODS
Six healthy male volunteers (mean age * SEM,
26.5 * 1.3 years) WE paid to participated in the
study after each gave informed consent. The cxperimctttal protocol and the Subject’s Consent Form was
,by the MassachusettsInstitute of Tcchnoi~ (MIT) Co~ttee oti the Use of Humans as Expcnmentd Subpxs. All vohtnteersreported that they
were free of habitual sleep disturbancesand thazthey
were dntg-fmc. Self-report questionnaires completed
by volunteerson each test day mgardhg thcii previous
nights’ sleep ‘htdkated that their mean bedtime wcurredat 1240 AM&22 minutes, mean sleep duration
was 7.2 A 0.32 hours, and mean estimated sleep onset latencyat the habitualsleep time was 21.6 Y 4.26
minutes.Subjectswere nonsmokersand were asked to
not consume alcohol or caffeine for 24 hours before
each test session. Meals (providedby the MIT CIinical ResearchCenter)reflecteda typicalAmericandiet:
15% protein, 35% fat, 50% carbohydrates; 3000 to
4000 calories per day.
lle study consisted of three double-blind and placebo-controlled exprimcnts. Treatment order for each
experiment was determined with use of a 3 X 3 Latin-
/
square dcs@ to counterbalance for order effects.
Each volunteer pa@ipatcd in a total of nine test sessions, with at kast 5 days elapsing betweensuczcssive
sessions. In the first cxperitnent, subjects undcnvcnt
three test sessions in whkh they received placebo or
mclatonin (0.3 .or 1.0 m~ NCQE Co., VCVCY, SwiCAand) in gelatia capsules, orally at 6 PM.In the second and third expdncnts they received the same
doses of melatoninor placeboat 8 or 9 PM.In the first
two ex@ments, the sleep test consisted of2.hours of
polysornnogmphicallyreeordcdsleep that began when
the lights were turned off 2 hours after administration
of mclatonin or placebo (i.e., at 8 or 10 PM).In the
thii experiment, subjects spent the night before the
test session in the Cliiical Research Center, and their
sleep was mordcd polysomnographicallytiom 11 PM
to 7 AM.On the following night they retired in darkness at 10 PM,1 hour after ingestion of melatonin or
p!~ 9 PM,and tkii SkCP W= ~fded
POlj’somnographicallyfrom 10 mt until 7 M the folIowing
motning.
For polysomnographic~rdings,
ekctroenccphalographic electrodes. placed accordiig to the International l(Y20 System (with tecmdings from C4-AI, C3A2, U-01, and @-02), and elcctr@od -*
~
submental ckctromyographicektrodes were used fw
sleep staging. SignaIs from the cktz0de5 and transducers were amplified by lkhanncl prcamplifier/multipkxor uttiw they were then digitized and mootded
(DigiTraccCarcSdccs Inc.; B6stdn,Mass.). ‘fMrtysccondcpocbs wercstaged according tothccritcriaof
Rcchtschaffimand Kalcs13:~,
stages 1,2,3, or ~
and rapid eye movement(REM) sleep. Skcp onset latency was definedas the timeelapsing betwekttthe time
that lights were turned off and the appearanceof three
consecutiveepochsof stage 1 sleep: or of one epoch of
any other skef) stage. Latency to REM SkCP was defined as the time elapsingbetween sleep onset and the
appeamnccof one epoch of REM sleep. timpkte sets
of polysontnographicxecxmdings
were obtainedfromall
six of the subjects, except as noted below, after txeatment at 8 and 9 PM and from two of the subjects afler
treatmentat 6 PM.(No polysomnographicrecordingwas
obtained for subject6 after he received 1.0 mg mclatonin at 9 tw.) To test the subjectiveresponsesof the voluntcm to treatment, subjects given me!atoninor placebo at 6 or 8 PMwereaskedat the end of eachsleep test
whetherthey thoughtthat theday’s treatmenthad been a
placebo or a hypnotic, and their answers were recorded.
On the morning after trea[ment, subjects completed
a battery of computerized performance tasks and
554
ZkiJwJw a al.
A
80
Table I. Effects of melatonin, ingested at 9 PM,on
DaSe”
60
40
‘4
Sub~ct No.
*
Sleep onset fatenq
1
-
20
0.0
.
60
40
20
0
1.0
B
0.3
1.0
Fii. 1. Effects of melatonin (iigested at 8 PM)on average (SEZvf)latency to skq oosel (A) aid SkfI $ta& 2 @).
●
p < O.tx)l.
mood inventories that previous studies have shown to
be adequate fOr evaluating Of the kvcl of Skp-.
Four C&kc Reaction Tii, Siile Auditoty Rcactiott Tii,
Rofik of Mood States, and Stanford
SIccphcsaScale (for details see Dollinaet al.lJ).
Becausc ofthchigh
variabili~ ofchamctm “ tic
akcp patterns among subjects, the JJOtJ_C
~a~
~t14 Wasuscd tocvahtatcdiffcmmccaasSociated with the three tnmtment conditions. Group
mean VaIues Wcte substituted fw tile Jnissiig data
points Iiotn subject 6 (1.0 sttg at 9 M). RC@OtJ
analysis wssusedtocvaluatc tbercktionship b@iccu
the sleep onset latency after Imatmeat and halhal
sleep onset Iatency.
.
R.IXULTS
Both doses of melatoningivca at 8 PM~lg. 1) or at
9 W (Table 1) significantlydccmscd sleep onset k+
tency and latencyto stage 2 sleep (p < 0.001) dative
to placebo, as assessed polysonmographically.The
hormone was qually effective in the two subjects
studied at 6 m. llus, latency to sleep onset after
tseatmentat 6 PMdecreawd h
57.3 ~“17.88 (SEM)
minutes (placebo) to 10.8 A 0.13 tninuta (0.3 mg
dose) or 8.5 A 1.50 minutes (1.0 mg dosek at 8 w,
latency decmscd from 29.4 A 10.77 minutes (placebo) to 6.4 & 1.88 minutes (0.3 mg dose) or 7.2 &
1.13 minutes (1.0 mg dose); and at 9 PM, latency
03 mg
Latency-to stage 2 (rein)
1
214
2.5
:
28
4
35
5
6.
6
59
17
6
13
10
2
12
:
4.
5
6
] mg
(mitt)
12
4
6
8
2
10
**
L_m
F
0.0
.
0.3
Placebo
187
23
23
34
5
56~
0 k
80
I
deep patterns*
Latency to REM sleep {min~
1
163
2
80
3103
4
63
41
:
141
8:
7
6
7
t’
95
:
70
48
106
dcmased from 54.8 A 27.39 minutes (placebo) to
7.1 A 1.61 JJJiJJUk5 (03mgdose)or6.0*
I.07miJJutcs(l.O mgdosc). Latencyt0sIeepqe2&
a more sensitive index of the hypnoticCf%ctof melatonia. At 6 PM,Iatency kreased fiotn 65.3 & 1438
minutes (placebo) to 19.0 A 125 JtdnUtcs (0.3 Jng
dose) or 14.0A 3.75 minutes.(1.Omg dosch at 8 JIM,
it decrcad from 33.8 a 10.O6JJ@teS @l&)
[O
7.2 & 1.% JJJiJIUte$ (0.3 mg dose) or 11.4 A 3.23
minutes (l.0mgdose~at9Wit~
from
61.25 x 3134 MifNJkS (placebo)to 10.1 A 2.17 minutes (0.3 mg dose) or 11.3 A 3.7 minutes (1.0 mg
dose). l-he effects of tbc physiologic(0.3 J@ and low
-logic
(1.0 mg) doses of mclatonin did not
ddhr significantly with mpect to any of tbe parametersmcasu@ thcmfotetbcbighcrh
didnotcnhiincethe hypnotic effect. We did not findstatistically
significant differences in latency to REM sleep ~
mclatonin or placebo dminimw .00 at 9 m, Jdtbough
in three of the siX subjects this intend .dccmased
~mcwhat afier administrationof the IOWCX
dose. ~able l).
The abtity of mclatonin to dcuwsc the sleep onset
latengy of any subja
varied in proportion to his sleep
Zba%z?wiw
a d.
555
8
.
200
)
150
100
50
0.0
.0
50
Sleep
F&2.’1herdadon
sesicy*
?00
150
0.3
1.0
200
latency
bpenthcrcductiofti
nskponsctla-
the ingesoott of 0.3 mg dose of mcktonia at
9 ru aod the sleep latency in the untreatedcondition.
Iatency after placebo administration(r= 0.99 for the
0.3 tngdose andr = 0.94 for the 1.0 mgdosq Fig.
2). and in propordonto his sdf-seportedsleep onset
latcacy at his usual bedtime (r = 0.86). ‘fbus, subjects who required more than 20 minutes to fdl asleep
after placebo t2eattnuttexhibited the more robust*
sponscs to the exogenous hormone(Table I). Analysis
of subjective slecpimas and of scaction times in se_@*Wtil@tYstitionti_~= matmutt (at 730 Or 93 AM)rcveakd no hangover effects of melatotdntreatment(Fig. 3).
None of the volunteersmistook the placebof~ melamtdnintheir aelf-tqmsts. At8w, fourofthesubjecta seceiviog the 0.3 mg dose and five of the subjectsteceiving thel.Omgdosc mct@zedthatthey
had been tmatcd with a hypnotic. Most subjects perceived the hypnoticeffectwithinan hour of mchttonht
ingestion.
DISCUSSION
These data show that low era! doses of mclatonin,
which were previouslyshown to increasesuum mclatotdrt concentrations to kvels normally ocauring at
stighc’z produce acutehypnoticeffects when given in
the evening (Fig. 1, Table I’).Moreover,.theseeffects
am discernibleboth subjcctkly and by stattdatdpolySOtlU)O~phiC m!thods. ThCSC obsctvations COtttpkmcttt our carlkr findingthat simi!ar small melatonin
doses given at noon dccmase sleep latency, as tncasumd electromcchanically,12and support the idea that
the physiologicincreasein blowt melatoninlevels that
occurs late in the evening, 1 to 2 bouts bcfote habitual
bedtime, is involvedin the mechanisms that normally
trigger sleep onset.
Normally. the daily alternation of environmental
0.0
0.3
1-0
0.0
0.3
1.0
350
300
250
Melatonin.
Dose. (rn.9)
Fig. 3. Moodandpufonnanceon the-g
aftermclatonht tmtmetm Simpk RcacdenT- (A~”IMile of Mood
Statc5(fdgucdi
scale)(B~ andFourChoii Reaction
Tii, lllMWrdat731m (open& @m9Nti(~d
hers).
lightand darkness, ~latcd throughthe eycs,ls adap
tivcly harmonizesthe rhythmicsex-don of melatonin
from the pine-algland with other cimdiatt rhythms.
l%e noctutd lekasc of mclatonin fi-om the pined
gIand is coincidentwith the habitual hours of sleep in
PCOpk With entrained 24-hour SkCp-WSkC rhythms.2
In bhd persons, deprived of thk cnvimmncntalzeitgebcr, endogenouslydsivcn circadian rhythms tend to
fmc-rutt and become, to wuying degrees, dissociated;
deep LWXUTRSdisrupted, and dafiime alertness is diminished. 16 However, in a blind patient who exhibited
free-running C“madianrhythms, the ddy pattern of
skcp propensity and the onset of mcdatonin scctetion
were found to exhibit a normal relationship. 17This as-
a.
alrwx.
$S6 zbdanuvaa d.
sociation supports the hypahcsis that melatonin is in-
)
volved in normal nocturnal sleeponset.
Becauserepeated daily doses of melatonincan shift
the phasing of the daily thythm in human mclatonin
kvcls,:* it has been suggested that this trcattncnt can
also, as a consequence, shVt the sleep rhythml*zi
(i.e., that the effect of exogenousmelatoninon skcp
is regulated by induced changes in the cndogcnous
rhythms). Thk does not seem to be a likely cxpkmation for-the changes in sleep latency observed hem
(Fig: 1; TabIq I) or in our previousstudy]2 in which
tnelatonin was administered at noon and sleep onset
measuredat 2 PM.l%e extent to whicha single dose of
mclatonin can shift the daily rnelatonin rhythm has
been mqsurcd with usc of repeateddaily administration of the hormone at various time points,2t or melatonin infusions over 3-hour intervals,= and found to
be less than 1 hour per by of treatment,regardless of
the time of day that melatonin was administered. Our
present and previous findings ‘2 show that a single
physiologic (0.3 mg) dose of melatonin can ~vokc
J
sleep onset 5 to 11 hours catiier than skep would otherwise occur. Similarly, Tzischinskyand Lavie,” using a pharmacologicdose of tndatonin (5 mg), found
that the hormone facilitated skcp onset and sleep propensity 2 hours after it was administaed at noon or at
S m. Such cffdcts arc clearly unrektcd to a gcncd
shiiincircadian rhythms. our6ndings andthoscof
the Israeli groups suggest that tbc induced ckvation
of circulating tndatonin concentrations triggas the
omW of sleep, rcgardks of the pmliling phase of
CndogeuousCiKadii rhythms. This acute Cffkct of
melatoninon skep, considered in view of the reported
increasein plasma melatonin kvels24and the incmasc
in urinary tnclatonin duting sleep &privation,Z sup
ports the idea that endogenous mclatottinmay scnm as
a link between circadian rhjthmicity and tk homcostatic mcchankms of skcp. This may account for the
obsenwd reduction of sleep latency as a finction of
sleep deficiencyreported by Catskadonand Demcnt.M
Thus a critical serum melatonin level maybe b@c to
normal nocturnalsleep inductionin humans.
In our studies, the extent to which mclatonin accelerated sleep onset in any subject varied with hii characteristic sleep latency in the untmawxl state. The
sources of intersubject variability in sleep onset latency are unknown but could be related.in part to dif-
ferences in subjects” characteristic 24-hour serum melatonin patterns, which were not documented in this
study. A similar relationship could also underlie the
well-known increase of sleep patho]ogy among older
People,z’ inasmuch as nocturnal mclatonin production
mmMhmmGi & lllsMrwncs
MN Iws
also declines with advancing age.=s Becauseon[y.
young volunteerswere involvedin our studks, wc do
not have data on possible agc-mlatcddifferencesin
the skepindueing eff~-of mclatonin. However. H&
mov et al.n fwnd that older peopk with insotia
have lower nocturnal melatonin kvels than thOSCof
young peopk and of older subjects withoutinsomnia.
Available &&
SUggCSt tbt
tk
SkC@dUCing
p~
of rne~atoninmay differ horn thoseof the bcnzodiazepincs. Bcnzodiazcpinesdectcasc the duration
of REM sleep after the singk ad-ministrationof a high
dose31 or ‘of longer-term administration of low
dos+~’; tky dSO ltXhlCC SIOW WVC SkCp,n thus
influencingskep quality. In our study, usnegatively
ing a single low mclatonindose, We obscivcd no sup
pression of REM skcp, and ,mme of the subjectsunde.rwcntREM sleep sooner after mclatortintmatmcnt
than after placebo (Table I). It is interestingto oote
that the bcnmdkepines reportedly also suppress the
nocturnal increase in plasma rnelatoninand may incrwsc daytime plasma melatotiht kvck.x= Such effects could account for the residual daytimesedation
that frequentlyoccurs *
benzodiazcpinetreatment,
as well as for the rebound insomnia that can follow
the terminationof qch treatment. hfusion of L-tryp
tophan3’-39or of Delta-skcpxnducing
Pcptidc,@
whit% can provoke SkCp OtlSCt, abo KCpOttdy inJn contrast,
crease cumulatingtnclatonin kv&4’4
dies
&dtWtC@C
blocking agatts””a or nmateroidal ~.
inflammatory dregs (e.g., aip”irin),-” whichdisturb
sleep, dccmasc blood melatoninkvck.
h the dcdgn of our Cxpcrinmts. the objective
“sleep tests” were Misted only I or 2 hoursafk ingestion of mclatoti, thus we lack data on the minimum latency of the hormone’s effect. However,selftepotts of the. volunteers indicated that their usual
latency to its hypnoticeffect was 25 to 60 minutes.In
previous polysomnographic studies of the Cff” of
melatonin on sleep latency positive results were obtained when melatonin was given 1 to 2 hotus bcfom
the cffkct was observed (80 mg6 and 5 mgz), and
negative results were obtained when it was administered 15 minutes before bedtime(1 or 5 mgs’~. Further studies am needed to determinethe timecourseof
the effect of physiologic melatonindoses on sleep latency.
One of the major problems with existing hypnotic
agents (e.g., the benzodiazcpines) is a hangover effect; that is, on the morning after treatment, patients
experience inappropriate sleepiness, changes in mood,
and diminished perforrnarm. In thk study, we used a
tests previously
shown to bC
battery of computerized
.-.
Zhibwva et cd. 557
●
changes inScnsk.iwtobmoodandpcrfbtm—
tto hangover
ducedby hypnotic agents. ‘fky SCVCSkd
cffkcts the morning after evening admittiktrrdonof
t
mclatonin.
Our findmgst1 (Table I; Fig. 1) strongly suggest
that the sleep onset, which is provoked by a single
dose of melatonitk tesu!ts not from its effect on biological t-hnistgmechanisms, but fmtn a dti
action of
the elevated ci@ating mclatonin per SC.
?
..
We thankJoseph McCarthy&r tcchnicat assistance,the
auning staff of the MIT aiikal RescamhCustcs for assistmce in experiments, and Digiiracc Cam Scrvkcs, Inc.,
Boston, Mass., for loan of the recording equipment.
Rqfemuzs
L Lcmu AB, Case JD. Me!atonin. Fcd Proc 196%19:
590-2.
2. Lynch HJ. WuqmanRJ, MoskowirzMA, ArcherMC,
Ho MH. DaiIy rhythm in human urinasy snclamnin.
science 197%181169-71.
3. w~
RI, Li~.HR.
Melatonin secretionas a
mcdhitor of ciscadii variationsin sleep and SIcepincss.
J Pined Rcs 198S?301-3.
4. Anton-Tay F. DiazL Fcrnandez-GuardiolaA. On the
effect of snclatordnupon human braim its pcmibk therapeutic il@@ons. Life Sci 1971;KM141-SO.
S._lLRudofs)h
J. ConshmchU. KcadclK.00thc
cffcctsof&dato&&skqandhehaviorinrn
an.Mv
B*~1197411:1~-9L
L Sleeplah6. Waldhawa F, SaMuB, Trinchmd-Lugan
oratosyinvestigations
on hypnotkpropdcs of mclato~n- ~108Y
@@ 19$W~Q22-6.
7. Vollrath~ ScnunP. GammdG. Sleepinductionby
intmnasalapplicationof snclatonin.Adv Biosci !981;
2%327-9.
8. James SP, McndelspnWB, Sack DA, RosenthalNE,
Wchr TA. The effect of mc!atonin on normal skcp.
Nc~108Y
198fil:41~.
9. James SP, Sack DA, Rosenthal NE, Mendckon WB.
Melatonin administrationin insomnia. Ncuropsychopbalmacology 199Q1:19-23.
10. Lkbcrman HR. WatdhauscrF. Garfield G, LynchHJ,
Wurtman RJ. Effectsof rnclatoninon human mood and
W-f ormancc. Brain Res 1984~23:201-7.
11. Dollins AB, Lynch W, Wurtman F/J, ti al. Effect of
pharmacological
daytimedoses of rnc!atonin on human
..
1~.
mood and performance. Psychopharmacology (Bert)
1993;1 12:490-6.
Dollins AB, Zhdanova IV. Wufiman W. Lynch W.
Dcng MH. Effectof inducing nocturnal serum mclatonin
concentmtions in daydrnc on skcp. mood. body
wmpcratum. and performance. Proc Nad Acad Sci
USA 1994:91 :[824-8.
Rcchtd@en A. KdcsA. Amanual ofstaddid
~*@@-~--fw*p
stages of human subj=ts. Los Angck Brain Information ScwkefBrain RcscamhInstitute, 1968:1-60.
14. McndcnhallW. Beaver RJ. Jntsoductionto probability
and statist@. Bostorc PWS-Ke@1991:614-8.
15. WurtmanW, AxclrodJ, Fmhcr JE. Melatonin synthesis in the pined gland effect of light mcdiicd
by she sympatheticncwous system.Science 1*,143:
x3.
1328-30.
16. Sack w
17.
18.
19.
20.
Lcwy AI. Blood Mu
Keith U),.Nakagawa
H. Circadii rhythm abnormalitiesin totally blii people incidence and clinical significance. J ah End@
&$lOl Mctab 199~75:127-34.
Nakagawa H, Sack M Lewy AL Sleep propensity
free-runs with the wmpcmue, mctatonin and cortisol
d@uns in a mtaftyblindpason. Steep 1992433(M
Sack RI+ L&y AL Mchtonin dminimation phase advanced cndogcnous rhythms in humans. Sleep Rcs
198%17396402.
Folkard SOArcndtJ, Aldhoua M, KcnncttH. Mclatonin
statiliscsslce
ponscttimc inablindnwn
withoutcn.
trammcnt of cordsol or tqxmurc
rhythms. Ncumsci
Lea 199Ql13:193-8.
Dahlitz M, Alvamz B, Vignau J, English J, Arcndt J,
Paskcs JD. Delayed Skcp phase syndrome tesponsc 13
Inclatonin. Lancet W91337:lf214.
21. @AJ.
saRL. uscofmclatonin to~and
trutof&a&mp hasc&sor&rs.h Touitou Y,
Arcndt J, Pcva P,cds. Mdatoninandthcpinal glad
tiombasic scicnce todinkal appliion. Amstdam
Excerpts M* 1993X5-9.
22 Zaidan~ GcotTiiaaM, Brun J, et aL Mclatoninis
able to iidiucnccits sccmdonin humans description
of a phase-mponsc awe. Ncumcndwsinology 1994;
6&los-12.
0, Lavie P. Mclatonin possess timc23. Tzischii
dcpcadcnthypnotk cffkcts, Sleep 1M,17:63845.
24. Salii-l%scualRJ, Ortega-SotoH, Hucrtdkladil]o, CamacbArmyo I. RoMan-RoldanG, Tarnarkin L. The
Cffcctof total’sleep deprivation on p[asma mclatonin
snd cortisol in hcaldsy human volumecrs. Skcp
1988;11:362-9.
Y, WetterbcrgL Me25. AkcrstcdtT, FrobcrgJA, Frii
htonin cxcswkm. body tcmpcraturc and subjective
dusirsg64 hours of sleep dcptivatiori. Psychosrousal
1~.4:219-2S.
mwocndocrinology
26. Carskadon MA. Dcmcnt WC. hkxtumat dc(crminants
>f daytime skcpincss.
Skcp 1982~:S73-81.
age related changes in sleep. h
27. Zcpclin H. Nod
3asc M, Wcitzman ED, cds. Sleep disordcrx basic
imd clinical research. New York: SP & !kicn[jfic Books
1983:43144.
28. 1guchi H,
Ka(o KI, [bayashi H. Agedepcndcn[ rcducin serum mdatonin concentrations in hcahhy hurnan subjcc~. J Clin Endocrino] Metab 1982:1:27-9.
1ion
.n
558
/
zbdanuvact d.
29. Grad BR. Rwncwaig R.llwrokofmcIstodII andscrotonin in @Ig update.Psychmcmdddogy
1993:18283-9S.
30. mimov 1.LaudooM. ZSSPCJ
N. u d. WXP ~.
31.
32.
33.
34.
35.
36.
37.
and mdatonin rhythms in elderly people [letter]. Br
Ma! J 19!WO%167.
KalesA. KalesJD. SchaIf MB, Tan TL. Hypnotks and
altered sleep-dreampattcrtw all night E133 studks of
Chloral hydrate, flwazcpam and mcthqwdonc. Ad
GUI Psychiatry 1970ZM9-25.
Dcmcnt WC, ZaICOncVP, HacklesE, Smythc H, Carskadon M. ‘Sleep laboratory and clinical studies with
flutaqam. In GamattiniS, Mussinin R Randall U),
bcnzodia@ncs. New York Raven Press,
cds. ~
1973599411.
Gs~
L Adam K. Borrow S, kiZ.ikOWSki C. The effects of two hypnoticson sleep, subjectivefccliigs and
skilled performance. Imksonant P. Gswald I,cds.
pharmacology of the states of aktncss. New York
-n
PrCSS,197%51-9.
Frcdcrickson PA, Kfuegcr BR. Insomnia associated
with specific poIysomnographicfindings. “k Krygcr
MI-I.RothT, -t
WC cds. ~pk$
and pmcticc
of sleep medic-be. PhiIadclphiz WB Saunders,
1989484-5.
Kabuto M, Namwa I. Saitoh Y. Nenhancement of plasma mchtonirt could be suppressed by bcnzodiazepinc.s & humans. Endodnol Jpll 198@3:
405-14.
McIntyc I, Burrows GD, NomnanTIL Suppmsion of
plasma mclatonin by a single dose of the buuodiazcpine alprdam in humans. Bid FsycMaq 1988;
24:105-8. ThodicfsdottirB, BjomssonJK, Kjcld M, Kristbjarnarsoo H. Effects of-mypmphm int daytime a.
Natropsychobiology1989~1:170-6.
38. ckorgc CF. Mil&rTW.HardyPJ. KtygcrMH. The d- s
f_
OfL+Sy@#Wt Ottd@I!WS k!CphtCStCybtnOfInak COmlatii with blood kwls. sleep 198%1234sS3.
39. Smeii-Hehnat
D. Spitwdw CL. Evaluation if
L-tSypt~
fo$ Ueatmau ofinsomnix arcvicw. p$y.
chopharmadogy
(.M)
198MM-7.
40. @f MV. Kastin M. llclta sleep inducing pcpctidc
(DSwk an update. Pc@dcs 198ml 16s-87.
41. HajakG. .jkthcr G. Blake J, c1 al. lbc inflttcnctof
L-tryptO@Sfl00 Pk
IllCkMlitt Sltd Sk!CP
itltMVUIOUS
in men. Pharmampsychiatsy199~S?k17-20.
42. Gukholl A, Pcvcf P. Impliition of tlyptophatt in the
stimulatoty effect of delta-slcep%tducingpcptidcon indole secretion tiotn pcrifu.ud mt pined glands. Biol
signals 19921:78-87.
43. Gukhou A, Zitouni M, Raynaud F, Siiux
V,
Gbarib ~ pevct P. Dcha-sk@nducing pcptidcstimulates mckttonin, 5-mcthoxytryptopholand scrotoaio scrxetion from pcrifuscd rat p“ti glands. Bid Signals
19921 :6s-77.
44. Cowcn PJ. Bevan JS. GosduI B, Elba SA. Treatment
with @-adrcnoccptorblockers reduces pmckniq .
concmtration. Br J Clht Phamacol 19U*19Z8-60.
45. Brismar K. Hykmdcr B, Eliin
K, RossncrS, Wct~
terberg L. Meiatoninsecretion rdated to side+ffects of
~blockcrs fmm the central nemous system. Acts Med
Stand 19mm525-30.
46. Murphy P, Badia P, Myers B~ BocckcrMR. WrightJr
EF. Nonstcroidalanti-iaflammat~ dntgs affect normal
~t?z
iO humans. Physid BChSV1991$$
47.
“.. ,
Mu@~ P, Mycm B, W@t IG Boccka M, Badii P.
Nonstcro”ti. anti-iotlammatory drugs and mclatonin
levels in humans [Abstrau]. Sleep Rcs 1993~413.